The relationship between MT-TR and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of March 4, 2024. The MT-TR gene encodes the mitochondrial transfer RNA (tRNA) for arginine. Defects of this tRNA lead to impaired mitochondrial translation, which leads to decreased synthesis of mtDNA-encoded subunits of oxidative phosphorylation (OXPHOS) complexes I, III, IV, and V, resulting in impaired OXPHOS enzyme activities.
MT-TR was first reported in relation to maternally inherited primary mitochondrial disease in 2004 in an individual with mitochondrial encephalomyopathy (PMID: 15286228). While various names have been given to the constellation of features seen in those with MT-TR-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MT-TR phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework.
Evidence supporting the gene-disease relationship between MT-TR and primary mitochondrial disease includes case-level data and experimental data. This curation included four variants (m.10406G>A, m.10437G>A, m.10438A>G, m.10450A>G) in four probands in four publications (PMIDs: 15286228, 17588757, 19809478, 22781096). Cybrid studies (PMID: 19809478) and single fiber testing (PMID: 22781096) further supported the pathogenicity of several of these variants. Age of onset was in childhood and features seen in affected individuals included muscle weakness, ataxia, hypotonia, epilepsy, global developmental delay and regression, pigmentary retinopathy, optic atrophy, renal insufficiency, and hypertrophic cardiomyopathy. Muscle biopsies showed ragged red fibers and COX-negative fibers and variable respiratory chain enzyme deficiencies.
The mechanism of pathogenicity appears to be loss of function due to altered RNA secondary structure. This gene-disease relationship is also supported by known biochemical function and in vitro functional assays demonstrating reduced rates of mitochondrial translation as a result of variants in MT-TR (PMIDs: 19809478, 33340416).
In summary, there is moderate evidence to support the relationship between MT-TR and primary mitochondrial disease. No convincing evidence has emerged that contradicts this gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 4, 2024 (SOP Version 10).
This gene-disease relationship was reevaluated on July 14, 2025 by this Expert Panel. As a result of this reevaluation, the classification did not change.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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